Increased adiposity and insulin resistance are characteristic of the metabolic syndrome, a disorder[unreadable] associated with accelerated vascular disease. The syndrome affects nearly a quarter of American adults,[unreadable] making it one of the most important current public health problems. Beyond the notion of insulin resistance,[unreadable] little is known about the specific mechanisms that promote vascular disease in this syndrome. We have[unreadable] made the observation in mice that defects in ATM (Ataxia Telangiectasia Mutated, the loss of which causes[unreadable] the disease ataxia telangiectasia) result in increased adiposity, elevated blood pressure, glucose intolerance[unreadable] and accelerated atherosclerosis, features of the metabolic syndrome. Tissues of these mice are insulin[unreadable] resistant and have increased activity of JNK, a mediator of insulin resistance and atherosclerosis. Treatment[unreadable] of mice with the anti-malarial drug chloroquine, an anti-inflammatory agent recently shown to activate ATM,[unreadable] activates p53, decreases JNK activity and reverses features of the metabolic syndrome in an ATM-dependent[unreadable] manner. Treatment of humans with the metabolic syndrome with low doses of the same drug[unreadable] activates ATM and improves features of the metabolic syndrome. To extend these observations, this[unreadable] project tests the hypothesis that the metabolic syndrome is characterized by an inadequate ATM[unreadable] response to the genotoxic stress of lipid accumulation in critical tissues. We will also test the related[unreadable] hypothesis that activation of ATM with low doses of chloroquine has beneficial effects on the[unreadable] metabolic syndrome.[unreadable] We will pursue the following specific aims:[unreadable] 1. To determine in mice if the effects of chloroquine on the metabolic syndrome are p53-dependent and[unreadable] define the mechanisms by which ATM affects vascular disease using bone marrow transplantation.[unreadable] 2. To determine in humans with the metabolic syndrome if the short term activation of ATM by chloroquine[unreadable] reverses features of insulin resistance and promotes an anti-atherogenic phenotype in macrophages.[unreadable] 3. To determine in humans with the metabolic syndrome if chronic activation of ATM by low dose chloroquine[unreadable] will decrease carotid artery intima-media thickness, a vascular marker of atherosclerosis.[unreadable] These studies have the potential to transform the care of people with the metabolic syndrome by[unreadable] developing a completely novel form of therapy, ATM activation by chloroquine, for vascular disease.